Pyrrolo[2,1-b][3,1] benzothiazepines and their use for the preparation of medicaments with antipsychotic activity

ABSTRACT

Compounds with formula (I) are described where the groups are as defined here below, as well as processes for their preparation, pharmaceutical compositions containing them and their use for the preparation of medicaments with antipsychotic activity.

[0001] The invention described herein relates to compounds for thepreparation of medicaments useful for the treatment of psychiatric andneurological disorders, to processes for their preparation and topharmaceutical compositions containing them as active ingredients. Inparticular, the invention described herein relates to compounds with apyrrolobenzothiazepine structure with typical and a typicalantipsychotic activity that can be formulated in pharmaceuticalcompositions intended for the treatment of acute and chronic psychoticstates.

BACKGROUND TO THE INVENTION

[0002] The involvement of dopamine and of the dopaminergic neurons in avariety of psychiatric and neurological disorders, has now beenextensively documented (E. R. Kandel, J. H. Schwartz, in “Principles ofNeural Science” Neurology”, Elsevier Science Publishing Co. New York,1985).

[0003] Among the various pathologies concerned, schizophrenia ischaracterised by a complex symptomatology caused by abnormalneurotransmission of the main dopaminergic pathways of the centralnervous system. The states of hallucination and deliria, described aspositive symptoms, are due to increased activity of the mesolimbicdopaminergic pathway, while the cognitive deficits and states of socialisolation, indicated as negative symptoms, are attributed to reduceddopaminergic neurotransmission in the frontal cortex.

[0004] The condition of hyperactivation of dopaminergicneurotransmission which underlies the acute and chronic psychotic statesof schizophrenia, acute psychoses of unknown aetiology, and the forms ofpsychosis and agitation that form part of the symptomatology of otherdiseases, is counteracted from a therapeutic point of view by the use ofclassic antipsychotic agents, otherwise called neuroleptics, the mostrepresentative of which are chlorpromazine (phenothiazine class) andhaloperidol (butyrophenone class).

[0005] Chlorpromazine was the first product to prove distinctlyeffective in the treatment of psychoses. This compound, initially usedas a sedative, proved capable of improving the condition of psychoticpatients, in that it was capable of inducing a particular indifferenceto environmental stimuli without altering the state of vigilance of thesubjects using it. Thanks to the enormous commercial success ofchlorpromazine, a search began in the '50s for new neuroleptic agentsand this soon led to the identification of other antipsychotic productsbelonging to many chemical classes.

[0006] The therapeutic efficacy of the neuroleptics is related to theirability to modulate the dopaminergic neurotransmission of the centralnervous system, via blockade of the dopamine receptors.

[0007] Their antipsychotic potency is directly proportional to theirability to bind and block dopamine receptors of subtype D₂ in thecerebral areas involved in abnormal functional dopaminergicneurotransmission. Moreover, psychopharmacology studies show that thedopaminergic hyperactivity that affects the mesolimbic pathway alsoinvolves the receptor subtypes D₁ and D₃. Consequently, theantipsychotic potency of a neuroleptic may also depend on its ability tointeract with these receptors, which are densely distributed on theneuronal endings in this pathway (J. Schwartz, Giro B., M. P. Martres &P. Sokoloff “Neuroscience” 4, 99-108; 1992).

[0008] From the clinical point of view, the antipsychotic efficacy ofthe numerous neuroleptic agents present on the market is qualitativelyequivalent in all cases. They differ only in their potency, in the sensethat, whereas some of them are effective at doses of only a few mg,others need to be administered at much higher doses.

[0009] The real differences between the various neuroleptic agentsdepend on their ability to favour the occurrence of unwanted sideeffects such as arterial hypotension, sedation and, above all, severemotor abnormalities, some of which are among the most frequentmanifestations associated with the clinical efficacy of the treatment.Whereas the former are due to the ability of the product to interactwith the alpha-1 adrenergic and H₁ histaminergic receptors,respectively, the latter, common to all neuroleptic agents, are due toblockade of the D₂ receptors of the nigrostriatal dopaminergic system.

[0010] Pharmacological and clinical studies have shown that thesimultaneous administration of neuroleptics and products with selectiveantagonist activity on serotoninergic 5-HT_(2a) receptors can increasethe antipsychotic efficacy of the former and attenuate the occurrence ofextrapyramidal symptoms as compared to treatment with neuroleptic agentsalone (G. F. Busatto and R. W. Kerwin “Journal of Psychopharmacology”11(1), 3-12; 1997).

[0011] Further developments in this sense have led to the generation ofdrugs with a mixed antagonist component, i.e. which are active ondifferent receptors.

[0012] Clozapine(8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) isan antipsychotic agent capable of simultaneously antagonising dopamineon D₂ receptors and serotonin on 5-HT₂ receptors. This new actionprofile, called “atypical”, allows schizophrenia to be treated with alower incidence of extrapyramidal symptoms (J. Med. Chem., 39, 1996, pp.1172-1188).

[0013] Unfortunately, the occurrence of cases of agranulocytosis haslimited the therapeutic use of this drug (Lancet. 1975, 2, 657).

[0014] Octoclothepine(8-chloro-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepine) isa compound partly endowed with “atypical” activity. Its pharmacologicalactivity has been studied in relation to the optical isomers of thiscompound (J. Med. Chem., 1991, 34, 2023-2030): a slightly greater effecton schizophrenia by the (S) form is unfortunately associated with agreater incidence of extrapyramidal effects, so that its use has beenwithdrawn from clinical trials. The (R) isomer presents a more“atypical” profile, with fewer side effects, but also an inferiorgeneral potency. Moreover, the two isomers prove to be endowed with thesame activity as 5-HT₂ and D₁ antagonists.

[0015] In view of the studies cited above, the need for antipsychoticagents with substantial therapeutic activity and without side effectsremains unsatisfied. In particular, the search continues forantipsychotic agents which present greater neuroleptic activity, a lowerincidence of extrapyramidal effects and minimal side effects(agranulocytosis; neutropaenia; sedation; weigh gain; costipation;urinary retention; dryness; hypotension).

ABSTRACT OF THE INVENTION

[0016] It has now been found that compounds of the 9-amino-substitutedpyrrolo[2,1-b][1,3]benzothiazepine class, particularly formula (I)compounds

[0017] where:

[0018] R=H, Cl, Br, F, I, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkyl,C₅-C₆ cycloalkyl;

[0019] R₁=C₁-C₄ dialkylamine, where the alkyl groups can be the same ordifferent from one another, 4-alkyl-1-piperazinyl,4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl,4-alkyl-1-homopiperazinyl;

[0020] R₂=H, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkyl, CHO, CH═NOH;

[0021] R₃=H, CHO;

[0022] are endowed with antipsychotic activity.

[0023] One object of the invention described herein therefore consistsin the formula (I) compounds indicated here above and theirpharmaceutically acceptable salts.

[0024] Another object of the invention described herein consists inprocesses for the preparation of formula (I) compounds.

[0025] A further object of the invention described herein is the use ofsaid compounds as medicaments useful as antipsychotic agents for thetreatment of psychiatric and neurological disorders, particularlydisorders related to increased activity of the mesolimbic dopaminergicpathway and/or mesocortical dopaminergic hypofunction such asschizophrenia in its positive and negative symptoms.

[0026] Still another object of the present invention is the use of saidcompounds as medicaments, in particular as antipsychotic agents, for thetreatment of psychosis, such as schizophrenia, paranoid states,manic-depressive states, affective disorders, social withdrawal,personality regression, hallucinations or cognitive dysfunctions.

[0027] Yet another object of the invention described herein consists inpharmaceutical compositions containing a formula (I) compound in amixture with at least one pharmaceutically acceptable vehicle and/orexcipient.

DETAILED DESCRIPTION OF THE INVENTION

[0028] In the formula (I) compounds, what is meant by the terms C₁-C₄are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and ter-butyl.

[0029] Among the formula (I) compounds, a first preferred group includesthose in which R₁ is 4-alkyl-1-piperazinyl. A second preferred groupincludes those in which R is H, Cl, Br, F, I.

[0030] In particular, when R=Cl, R₁=4-metil-piperazin, R₃=H, R₂=H thecompounds are typical antipsychotics, while for R=H,F; R₂=H, CHO, CH₃;R₃=H; R₁=4-methyl-1-piperazinyl, the compounds are a typicalantipsychotics.

[0031] Among typical antipsychotics, one particularly preferred compoundis 7-chloro-9-(4-methyl-1-piperazinyl)pyrrolo[2,1-b][1,3]benzothiazepine(hereinafter also referred to as ST1508), particularly the maleate(hereinafter also referred to as ST1699).

[0032] Preferred compounds of formula (I) with antipsychotic a typicalactivity, according to the invention are:

[0033] 9-(4-methyl-1-piperazinyl) pyrrolo[2,1-b][1,3]benzothiazepine(ST1899);

[0034]7-fluoro-9-(4-methyl-1-piperazinyl)pyrrolo[2,1-b][1,3]benzothiazepine(ST1928)

[0035]1-Methyl-9-(4-methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine(ST2092).

[0036] The compounds according to the invention described herein areprepared starting from the formula (Ia) compound

[0037] where R and R₂ are as defined above for the formula (I) compound,which is reacted with the desired amine R₁H as defined for the R₁ groupto yield the formula (I) compounds.

[0038] The preparation of the formula (Ia) compound is described inpatent application WO 00/06579, filed in the name of the applicant.

[0039] The transformation from compound (Ia) into compound (I) iseffected with known techniques, but it has been seen that the reactionis conveniently achieved by treating compound (Ia) with amine R₁H in thepresence of Lewis acids, e.g. triflates, such astrimethylsilyltrifluoromethane sulphonate, or protic acids, such assulphonic acids, e.g. p-toluene sulphonic acid.

[0040] The reaction is conducted in a solvent inert to the reagents andthe reaction products, or, preferably, amine R₁H can be used in relationto compound (Ia) in an excess such as to constitute the reaction medium.The reaction parameters are not critical and can be determined by atechnician with average experience in the field on the basis of his orher own general knowledge of the subject. For example, the molar ratiosof compound (Ia) to amine R₁H may range from 1:1 to an excess of aminein the sense referred to above. The reaction temperature will beselected also in relation to the type of reagents used, their molarratios, and the optional presence of a solvent, in which case it mayeven be as high as the boiling temperature of the solvent, providingthis does not lead to decomposition of the reagents themselves. Thereaction times are selected on the basis of the parameters outlinedabove and will be such as to complete the reaction. Attempts to optimisethe reaction do not constitute an additional experimental burden and arepart of the normal techniques used in chemical synthesis.

[0041] The isolation and purification of the formula (I) compound areaccomplished with normal known procedures.

[0042] In a first preferred embodiment of the invention, the formula(Ia) compound is reacted with amine R₁H, using the latter as a reactionmedium, when its physicochemical characteristics so permit. The triflatepreferred is trimethylsilyltrifluoromethane sulphonate. The reactiontemperature is approximately 120° C. and the reaction time approximately3 hours.

[0043] In a second preferred embodiment of the invention, the formula(Ia) compound is reacted with amine R₁H, using the latter as thereaction medium, when its physicochemical characteristics so permit. Thepreferred sulphonic acid is p-toluene sulphonic acid. The reactiontemperature is approximately 180° C. and the reaction time approximately1-2 hours.

[0044] Objects of the invention described herein are pharmaceuticalcompositions containing as their active ingredient at least one formula(I) compound, alone or in combination with one or more formula (I)compounds, or, said formula (I) compound or compounds in combinationwith other active ingredients useful in the treatment of the diseasesindicated in the invention described herein, for example, other productswith selective antagonist activity on the serotoninergic 5-HT_(2a)receptors, also in separate dosage forms or in forms suitable forcombined therapy. The active ingredient according to the inventiondescribed herein will be in a mixture with suitable vehicles and/orexcipients commonly used in pharmacy, such as, for example, thosedescribed in “Remington's Pharmaceutical Sciences Handbook”, latestedition. The compositions according to the invention will contain atherapeutically effective amount of the active ingredient. The doseswill be determined by an expert in the field, e.g. clinician or primarycare physician, according to the type of disease to be treated and thepatient's condition, or concomitantly with the administration of otheractive ingredients. By way of an example, we may indicate doses rangingfrom 0.1 to 100 mg/kg.

[0045] Examples of pharmaceutical compositions are those that permitoral, parenteral, intravenous, intramuscular, subcutaneous ortransdermal administration. Pharmaceutical compositions suitable for thepurpose are tablets, rigid or soft capsules, powders, solutions,suspensions, syrups, and solid forms for extempore liquid preparations.Compositions for parenteral administration are, for example, all theintramuscular, intravenous and subcutaneous injectable forms, and thosein the form of solutions, suspensions, and emulsions. We should alsomention the forms presenting controlled release of the activeingredient, whether as oral administration forms, tablets coated withsuitable layers, microencapsulated powders, complexes withcyclodextrins, depot forms, e.g. subcutaneous ones, as depot injectionsor implants.

[0046] The following examples further illustrate the invention.

EXAMPLE 1 a)7-chloro-9-(4-methyl-1-piperazinyl)pyrrolo[2,1-b][1,3]benzothiazepine(10b) (ST1508)

[0047]

[0048] Procedure A)

[0049] To a mixture of ketone [9b] (4.5 g; 18 mmol) andN-methylpiperazine (15 ml) was added drop-wisetrimethylsilyltrifluoromethane sulphonate (5.7 mL; 31.5 mmol) in 5minutes.

[0050] The reaction temperature was brought up to 120° C. The reaction,monitored via TLC, was completed in 3 hours. The reaction mixture wasleft to cool at ambient temperature and the resulting solid mass wasdissolved in methylene chloride (50 mL) and washed with water (2×30 mL).The organic phase was anhydrified on sodium sulphate and filtered.Evaporation of the solvent at reduced pressure enabled a crude reactionproduct to be recovered, which, when chromatographed on silica gel(n-hexane/ethyl acetate 50:50) finally yielded 4.7 g of the titlecompound.

[0051] Yield: 78%

[0052] TLC (AcOEt) Rf=0.25; MP: 127÷128° C.

[0053]¹H-NMR (300 MHz, CDCl₃) δ 7.6 (d, 1H, J=2.1 Hz); 7.4 (d, 1H, J=8.5Hz); 7.2 (dd, 1H, J₁=8.4 Hz, J₂=2.0 Hz); 6.7 (m, 1H); 6.6 (m, 1H); 6.2(m, 1H); 6.1 (m, 1H); 2.9 (m, 4H); 2.6 (m, 4H); 2.3 (s, 3H).

[0054]¹³C-NMR (300 MHz CDCl₃) δ 143.8; 140.5; 137.9; 134.8; 133.2;129.8; 129.6; 127.9; 123.2; 112.7; 111.6; 111.2; 55.2; 50.1; 46.2.

[0055] Elemental analysis: (C₁₇H₁₈ClN₃S): compliant.

[0056] Procedure B)

[0057] A mixture of ketone [9b] (0.15 g; 0.6 mmol), N-methylpiperazine(0.18 g; 1.8 mmol) and p-toluene sulphonic acid (0.296 g; 1.56 mmol) washeated to 180° C.

[0058] The reaction, which rapidly took on a dark colouring, wascompleted in 1.5 hours. After cooling at ambient temperature, theresulting solid mass was dissolved in methylene chloride (10 mL) andwashed with water (2×10 mL). The organic phase was anhydrified on sodiumsulphate and filtered. Evaporation of the solvent at reduced pressureyielded a crude reaction product which, when chromatographed on silicagel (n-hexane/ethyl acetate 50:50), yielded 0.10 g of the titlecompound.

[0059] Yield: 50%

EXAMPLES 2-13

[0060] The synthesis of products 2-13 has been carried out followingapproaches described in schemes 1

R R¹ R² R³ n ST 2 H Me H H 1 1899 3 H Me CHO H 1 2091 4 H Me CHO CHO 12147 5 H Me Me H 1 2092 6 H Me CH═NOH H 1 2129 7 H Me CH₂OH H 1 2096 8 HMe CH₂O/Pr H 1 2095 9 Cl Et H H 1 2148 10  Cl Me H H 2 2149 11  Br Me HH 1 2093 12  Br Et H H 1 2150 13  F Me H H 1 1928

[0061] R¹ in the above table identifies the 4-alkyl substituent on thepiperazine ring.

[0062] 9-(4-Methylpiperazin-1-yl) Pyrolo [2,1-b][1,3]benzothiazepine (1)(ST1899)

[0063] A solution of 9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-one(0.24 g, 1.11 mmol), N-methylpiperazine (0.55 mL, 0.50 g, 4.99 mmol) andtrimethylsilyl triflate (0.55 mL, 0.68 g, 3.05 mmol) was heated at 120°C. under stirring, after a few minutes further 0.55 mL ofN-methylpiperazine were added and the reaction was kept for 3 hours at120° C. After that time water was added and was extracted withdichloromethane. The organic layer was dried over sodium sulphate,filtered and evaporated to give the crude product that was purified bymeans of a flash chromatography (20% methanol in ethyl acetate) toafford 0.114 g of the pure title compound as a yellowish solid (84%yield).

[0064]¹H NMR (CDCl₃) δ 7.65 (m, 1H), 7.50 (m, 1H), 7.34-7.22 (m 2H),6.75 (m, 1H), 6.20 (m, 1H), 6.12 (m, 1H), 2.89 (m, 4H), 2.53 (m, 4H),2.34 (s, 3H).

[0065] Elemental analysis (C₁₇H₁₉N₃S): compliant.

[0066]9-(4-Methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine-1-carbaldehyde(2) (ST2091)

[0067] A mixture of phosphorus oxychloride (50.70 μL, 0.08 g, 0.54 mmol)and N-methylformanilide (67.15 μL, 0.07 g, 0.54 mmol) was stirred for 30minutes at room temperature. Then solid (1) (0.12 g, 0.42 mmol) wasadded and the resulting mixture was stirred overnight at roomtemperature. Then water was added and the water phase was extracted withdichloromethane (3×2.5 mL). Combined organic layers were dried oversodium sulphate, filtered and evaporated. Purification was accomplishedby means of flash chromatography (5% methanol in dichloromethane) andafforded 0.05 g of the pure desired product as a yellowish crystallinesolid (37% yield).

[0068]¹H NMR (CDCl₃) δ 9.45 (s, 1H), 7.65 (m, 1H), 7.46 (m, 1H), 7.32(m, 2H), 7.04 (s, 1H), 6.93 (d, 1H, J=3.9 Hz), 6.24 (d, 1H, J=4.3 Hz),3.15-2.95 (m, 4H), 2.57 (m, 4H), 2.35 (s, 3H).

[0069] MS m/z 325 (M⁺), 256, 81, 69 (100), 41.

[0070] Elemental analysis (C₁₈H₁₉N₃OS): compliant.

[0071]9-(4-Methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine-1,10-dicarbaldehyde(3) (ST2147)

[0072] A mixture of phosphorus oxychloride (18 μL, 30 mg, 0.198 mmol)and N-methylformanilide (24 μL, 26 mg, 0.198 mmol) was stirred for 30minutes at room temperature. Then solid (1) (30 mg, 0.100 mmol) wasadded and the resulting mixture was stirred overnight at roomtemperature. Then water was added and the water phase was extracted withdichloromethane (3×2.5 mL). Combined organic layers were dried oversodium sulphate, filtered and evaporated. Purification was accomplishedby means of flash chromatography (5% methanol in dichloromethane) andafforded 11.3 mg of the pure desired product as a yellowish crystallinesolid (35% yield).

[0073]¹H NMR (CDCl₃) δ 9.68 (s, 1H), 9.42 (s, 1H), 7.59 (m, 2H), 7.42(m, 2H), 6.87 (m, 1H), 6.31 (m, 1H), 3.70-3.62 (m, 4H), 2.59 (m, 4H),2.38 (s, 3H).

[0074] MS m/z 353 (M⁺), 324, 295, 83, 70 (100), 57, 43.

[0075] Elemental analysis (C₁₉H₁₉N₃O₂S): compliant.

[0076]1-Methyl-9-(4-methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine(4) (ST2092)

[0077] To a solution of (2) (0.035 g, 0.107 mmol) in absolute ethanol(0.70 mL), hydrazine monohydrate (182 μL, 0.019 g, 3.74 mmol) was added.The resulting mixture was stirred at reflux for 1 hour. After that timethe solvent was removed under vacuum; the yellow solid obtained wasdissolved in toluene (0.76 mL) and potassium tert-butoxyde (0.036 g,0.321 mmol) was added. The reaction mixture was refluxing for further 8hours. Then water was added, the organic phase was separated and theaqueous phase was extracted with dichloromethane; combined organiclayers were dried over sodium sulphate, filtered and evaporated. Thecrude product obtained was chromatographed (20% methanol inethylacetate). The desired pure product was obtained in a yield of 60%.

[0078]¹H NMR (CDCl₃) δ 7.62 (m, 1H), 7.48 (m, 1H), 7.26 (m, 2H), 6.32(s, 1H), 6.03 (m, 1H), 5.90 (m, 1H), 2.89 (m, 4H), 2.53 (m, 4H), 2.34(s, 3H), 2.20 (s, 3H).

[0079] MS m/z 311 (M⁺), 256, 213, 98, 69, 55 (100).

[0080] Elemental analysis (C₁₈H₂₁N₃S): compliant.

[0081]1-Methylenoxime-9-(4-methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine(5) (ST2129)

[0082] To a solution of (2) (0.010 g, 0.031 mmol) in dichloromethane(1.00 mL), hydroxylamine hydrochloride (0.043 g, 0.062 mmol) andpyridine (5 μL, 0.049 g, 0.062 mmol) were added. The reaction mixturewas stirred 1 hour at room temperature then dry potassium carbonate(0.008 g, 0.062 mmol) was added and the mixture was stirred for further72 hours. After that time hydroxylamine hydrochloride (0.043 g, 0.062mmol) and dry potassium carbonate (0.017 g, 0.124 mmol) were added andthe solution was stirred at 25° C. overnight. Then water was added, theorganic phase was separated and the aqueous phase was extracted withdichloromethane; combined organic layers were dried over sodiumsulphate, filtered and evaporated. The crude product obtained waschromatographed (10% methanol in ethyl ether) to afford 2.5 mg of thedesired product. (17% yield).

[0083]¹H NMR (CDCl₃) δ 7.80 (s, 1H);7.68 (m, 1H), 7.48 (m, 1H), 7.30 (m,2H), 6.94 (s, 1H), 6.38 (d, 1H, J=3.9 Hz), 6.15 (d, 1H, J=3.8 Hz), 3.02(m, 4H), 2.62 (m, 4H), 2.40 (s, 3H), 2.20 (s, 3H).

[0084] MS m/z 340 (M⁺), 323, 297, 225, 99, 70 (100), 56, 43.

[0085] Elemental analysis (C₁₈H₂₁N₄OS): compliant.

[0086]1-Hydroxymethyl-9-(4-methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine(6) (ST2096)

[0087] To a solution of (2) (17 mg, 0.052 mmol) in absolute ethanol(2.36 mL), sodium borohydride (7.13 mg, 0.188 mmol) was added. Theresulting mixture was stirred overnight at room temperature. After thattime the solvent was removed, the residue was treated with water and thesolution was extracted with dichloromethane; combined organic layerswere dried over sodium sulphate, filtered and evaporated. The crudeproduct obtained was chromatographed (10% methanol and 10% triethylaminein ethyl acetate) to afford 9.5 mg of the desired pure product (yield58.8%).

[0088]¹H NMR (CDCl₃) δ 7.63 (m, 1H), 7.49 (m, 1H), 7.29 (m, 2H), 6.76(s, 1H), 6.14 (d, 1H, J=3.7 Hz), 6.05 (d, 1H, J=3.8 Hz), 4.51 (m, 1H);3.05 (m, 4H); 2.47 (m, 4H), 2.32 (s, 3H).

[0089] MS m/z 327 (M⁺), 296, 225, 198, 87, 70 (100), 58.

[0090] Elemental analysis (C₁₈H₂₁N₃OS): compliant.

[0091]1-Isopropoxymethyl-9-(4-methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine(7) (ST2095)

[0092] To a solution ofN-[9-(4-methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine-1-yl]-N-tosylhydrazyne(37 mg, 0.075 mmol) in 2-propanol (4.0 mL), sodium borohydride (13 mg,0.449 mmol) was added in portions while stirring at 0° C. The resultingmixture was stirred for 24 hours at reflux then for 48 hours at roomtemperature. After that time the solvent was removed, the residue wastreated with water and the solution was extracted with dichloromethane;combined organic layers were dried over sodium sulphate, filtered andevaporated to give the crude product which was chromatographed (0.8%methanol in ethyl acetate) to afford pure (7) as yellowish crystals(51.4% yield).

[0093]¹H NMR (CDCl₃) δ 7.63 (m, 1H), 7.48 (m, 1H), 7.27 (m, 2H), 6.76(s, 1H), 6.14 (m, 1H), 6.05 (m, 1H), 4.37 (s, 1H); 3.60 (m, 1H), 2.52(m, 4H), 2.92 (m, 4H), 2.34 (s, 3H), 1.17 (s, 3H), 1.14 (s, 3H).

[0094] MS m/z 369 (M⁺) (100), 326, 310, 296, 97, 70.

[0095] Elemental analysis (C₂₁H₂₇N₃OS): compliant.

[0096]7-Chloro-9-(4-ethylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine (8)(ST2148)

[0097] Starting from7-chloro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-one (0.19 g,0.76 mmol) and N-ethylpiperazine (0.70 mL, 6.13 mmol), the titlecompound was obtained following the above described procedure for (1).After purification, 0.19 g of the desired product were obtained as awhite solid (yield 74%).

[0098]¹H NMR (CDCl₃) δ 7.62 (d, 1H, J=1.9 Hz), 7.41 (d, 1H, J=8.0 Hz),7.22 (d, 1H, J=8.0 Hz), 6.73 (m, 1H), 6.57 (s, 1H), 6.20 (m, 1H), 6.10(m, 1H), 2.88 (m, 4H), 2.50 (m, 6H), 1.10 (t, 3H, J=7.1 Hz).

[0099] Elemental analysis (C₁₈H₂₀ClN₃S): compliant.

[0100]7-Chloro-9-(4-methylhexahydro-1H-1,4-diazepin-1-yl)pyrrolo[2,1-b]-[1,3]benzothiazepine(9) (ST2149)

[0101] The title compound was obtained following the above describedprocedure for (1), starting from7-chloro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-one (0.03 g,0.12 mmol) and 1-methylhomopiperazine (0.06 mL, 5.41 mmol). Afterpurification the desired product was obtained with a yield of 41%.

[0102]¹H NMR (CDCl₃) δ 7.53 (d, 1H, J=2.4 Hz), 7.43 (d, 1H, J=8.8 Hz),7.22 (dd, 1H, J=8.4, 2.4 Hz), 6.75 (m, 1H), 6.55 (s, 1H), 6.19 (m, 1H),6.11 (m, 1H), 3.20 (m, 4H), 3.15-2.61 (m, 4H), 2.40 (s, 3H), 1.95 (m,2H).

[0103] MS m/z 345 (M⁺) (100), 205, 140, 97.

[0104] Elemental analysis (C₁₈H₂₀ClN₃S): compliant.

[0105]7-Bromo-9-(4-methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine(10) (ST2093)

[0106] A solution of7-bromo-9,10-dihydropyrro[2,1-b][1,3]benzothiazepin-9-one (0.10 g, 0.34mmol), N-methylpiperazine (0.169 mL, 1.53 mmol) and trimethylsilyltriflate (0.169 mL, 0.935 mmol) was heated at 120° C. under stirring,after a few minutes further 0.50 mL of N-methylpiperazine were added andthe reaction was kept for 3 hours at 120° C. After that time water wasadded and the water phase was extracted with dichloromethane. Theorganic layer was dried over sodium sulphate, filtered and evaporated togive the crude product that was purified by means of flashchromatography (20% methanol in ethyl acetate) to afford 0.114 g of thetitle compound as a yellowish solid (84% yield).

[0107]¹H NMR (CDCl₃) δ 7.76 (s, 1H),7.37 (m, 2H), 6.73 (m, 1H),6.57 (m,1H), 6.20 (m, 1H), 6.10 (m, 1H), 2.87 (m, 4H), 2.53 (m, 4H), 2.35 (s,3H); Elemental analysis (C₁₇H₁₈BrN₃S) C, H, N.

[0108]7-Bromo-9-(4-ethylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine (11)(ST2150)

[0109] The title compound was obtained following the above describedprocedure for (10), starting from7-bromo-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-one (0.10 g,0.34 mmol), N-ethylpiperazine (0.169 mL, 1.53 mmol) and trimethylsilyltriflate (0.169 mL, 0.935 mmol); then further 0.50 mL ofN-ethylpiperazine were added. After purification 0.125 g of the desiredpure product was obtained as a white solid (94% yield).

[0110]¹H NMR (CDCl₃) δ 7.76 (s, 1H), 7.36 (s, 1H), 7.26 (s, 1H), 6.75(m, 1H), 6.57 (s, 1H), 6.21 (m, 1H), 6.10 (m, 1H), 2.90 (m, 4H),2.60-2.46 (m, 6H), 1.12 (t, 3H, J=7.0 Hz); MS m/z 390 (M⁺+H), 356, 137,111, 97, 84 (100), 69, 57.

[0111] Elemental analysis (C₁₈H₂₀BrN₃S): compliant.

[0112]7-fluoro-9-(4-methyl-1-piperazinyl)pyrrolo[2,1-b][1,3]benzothiazepine(ST1928)

[0113] The title compound was prepared starting from7-fluoro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-one andfollowing the procedure A as described in example 1.

[0114] Molecular Pharmacology

[0115] a) Evaluation of Ability to Interact with D₁, D₂, D₃ and 5HT_(2a)Receptors.

[0116] Interaction with D₁, D₂, D₃, and 5HT_(2a) receptors was studiedusing various different cerebral areas (striate D₁ and D₂; olfactorytubule D₃; prefrontal cortex 5HT_(2a)) according to the method describedin the literature (Campiani et. al. J. Med. Chem. pp.3763-3772,1998).

[0117] Interaction with the D₁ receptor was evaluated using theradioligand [³H]-SCH 23390 (0.4 μM) and the aspecific binding wasdetermined in the presence of (−)-cis-flupentixol (10 μM). For the D₂receptor ³H-spiperone (0.2 nM) was used and the aspecific binding wasdetermined in the presence of 100 μM of (−) sulpyride.

[0118] As regards the D₃ receptor, the radioligand chosen was³H-7-OH-DPAT which was used at the concentration of 0.2 μM and theaspecific binding was obtained in the presence of dopamine 1 μM. Lastly,interaction with 5HT_(2a) was evaluated using ³H-ketanserine (0.7 μM)and the aspecific binding was determined in the presence of methysergide1 μM.

[0119] b) Evaluation of Ability to Interact with the H₁ Histamine andα₁-Adrenergic Receptors.

[0120] Interaction with H₁ Receptors

[0121] Interaction with H₁ receptors was studied using rat cortexmembranes incubated with [³H]-pyrilamine at a concentration of 1 nM inphosphate buffer 50 mM pH 7.4 for 60 minutes at 30° C., according to theprocedure described by Hill (S. J. Hill, P. C. Emson, J. M. Young “J.Neurochemistry” 31, 997-1004; 1978). Aspecific binding was determined inthe presence of 100 μM of pyrilamine.

[0122] Interaction with α₁ Receptors

[0123] The interaction with β₁-adrenergic receptors was evaluated on ratcortex using the radioligand [³H]-prazosin (0.2 nM), according to theprocedure described by Greenglass (P. Greenglass, R. Bremner “Eur. J.Pharmacol.” 55, 323-326; 1979).

[0124] Aliquots of membrane protein were incubated for 30 minutes at 25°C. with the radioligand and the aspecific binding was determined in thepresence of 100 μM of prazosin.

[0125] General Pharmacology

[0126] Evaluation of Catalepsy

[0127] The test was performed on Wistar male rats (N=7 animals);catalepsy was evaluated by means of a metal bar measuring 0.6 cm indiameter positioned at a distance of 10 cm from the work surface. Thesubstance studied, in the form of maleic acid salt (ST1699), wasadministered subcutaneously 30 minutes prior to the evaluation. Thesubsequent evaluation times were 60, 90, 120, 180, 240, and 300 minutesafter administration. The test consisted in positioning the animal withits forepaws on the bar and measuring the time the animal remainedattached to the bar, considering an end-point of 60 seconds (N. A. Mooreet al. Journal of Pharmacology and Experimental Therapeutics Vol. 262pp. 545-551 (1992)).

[0128] Results and Discussion

[0129] Table 1 gives the means and standard deviation of the affinityvalues expressed as Ki (nM) of the study product ST1508 for thedopaminergic receptors D₁, D₂ and D₃; the serotoninergic receptor5-HT_(2a), the alpha₁-adrenergic receptor and the H₁ histaminergicreceptor.

[0130] In addition, the table presents the affinity values for theabove-mentioned types of receptors for the compound haloperidol, as areference belonging to the neuroleptic drug class, for the purposes ofverifying the typical antipsychotic profile of the product studied.TABLE 1 D₁ D₂ D₃ 5-HT_(2a) α¹ H₁ K_(i) ± ds K_(i) ± ds K_(i) ± ds K_(i)± ds K_(i) ± ds K_(i) ± ds ST1508 1.9 ± 0.1 0.43 ± 0.04 2.0 ± 0.1 0.34 ±0.05 4.3 ± 0.1  2.7 ± 0.02 Haloperidol 318 ± 59  4.81 ± 1.0  18.2 ± 1.5  164 ± 23.6  12 ± 2.5   386 ± 0.001

[0131] The product ST1508 shows a substantial ability to interact withthe receptor types considered. In particular, it can be seen that thelow affinity values for the D₁, D₂ and D₃ receptors indicate a strongreaction of the product with the dopaminergic system, which is evenbetter than that found for the haloperidol receptor profile.

[0132] This particular receptor profile enables the compounds accordingis to the invention described herein to be defined as classicantipsychotic agents. In fact, the D₁, D₂ and D₃ receptor affinityvalues indicate that the compounds are capable of exerting an effect onthe hyperactivity condition of the mesolimbic dopaminergic systemresponsible for acute and chronic psychotic states.

[0133] Table 2 gives the means and standard deviation of the affinityvalues expressed as Ki (nM) of the preferred compounds ST1988, ST1928and ST2092 for the dopaminergic receptors D₁, D₂ D₃; and forserotoninergic receptor 5-HT_(2a). Typical (haloperidol) and a typical(Clozapine, Olanzapine) antipsychotics binding affinities arerepresented. TABLE 2 5-HT_(2a) D₁ D₂ D₃ Compound Ki (nM) ± ds Ki (nM) ±ds Ki (nM) ± ds Ki (nM) ± ds Clozapine 10 ± 1  353 ± 35  250 ± 57  319 ±65  Olanzapine 4 ± 1  85 ± 3.5 69 ± 17   26 ± 7.75 Haloperidol 164 ± 24 318 ± 59  4.8 ± 1    18 ± 1.5 ST1508 0.34 ± 0.05 1.9 ± 0.1 0.43 ± 0.042.0 ± 0.1 ST1899 0.6 ± 0.1  19 ± 1.3  17 ± 4.5   8 ± 0.5 ST1928 0.35 ±0.04  7.7 ± 0.58 8.5 ± 5   2.70 ± 0.10 ST2092  1.1 ± 0.05 154 ± 116 126± 15  18 ± 1 

[0134] Preferred compounds display high affinity at 5-HT₂ receptor as atypical reference antipsychotics Clozapine and Olanzapine anddifferently from Haloperidol.

[0135] Moreover, ST1899, ST1928 and ST2092 binding affinity at 5 HT₂receptor is greater than D₂ dopamine receptor, which resembles thebinding characteristics of a typical antipsychotics.

[0136] In vitro, classification of a typical and typical antipsychoticdrugs could be done considering 5-HT₂ versus D₂ affinity (pKi values)ratio and Log Y score (Meltzer H Y et al. “Classification of typical andatypical antipsychotics drugs on the basis of dopamine D ₁ , D ₂ andserotonin ₂ pKi values” J. Pharm. Exp. Ther. 1989, 251, 238-246).Antipsychotic with a 5-HT₂ versus D₂ affinity (pKi values) ratio greaterthan 1.12 and Log Y score smaller than 6.48 has an a typical profile. Intable 3 the affinity ratios and Log Y score of typical (Haloperidol) anda typical antipsychotics (Clozapine and Olanzapine) are compared tothose of preferred compounds. ST1899, ST1928, ST2092 display an atypical profile in similar fashion to Clozapine and Olanzapine.Furthermore, ST2092 display an a typical profile better than referencecompounds.

[0137] About ST1508, 5-HT₂ versus D₂ affinity ratio and LogY scorevalues confirm a typical profile for this compound. Despite of highcapacity interaction at 5HT₂ receptor (similarly to ST1928, ST1899, andST2092), ST1508 has a more marked dopaminergic profile than that of itsdirect structural analogues ST1899 ST1928 and ST2092. TABLE 3 5-HT₂/D₂5-HT_(2a) D₁ D₂ D₃ Ratio pKi Compound pKi pKi pKi pKi values LogYClozapine 8.00 6.45 6.60 6.50 1.21 3.89 Olanzapine 8.4 7.07 7.16 7.411.17 4.69 Haloperidol 6.78 318 8.32 7.74 0.82 9.14 ST1508 9.47 8.72 9.378.70 1.01 8.20 ST1899 9.19 7.71 7.76 8.08 1.18 4.98 ST1928 9.46 8.118.07 8.57 1.17 5.36 ST2092 8.95 6.81 6.9 7.74 1.30 3.19

[0138] These results render the compounds ST1899 ST1928 and ST2092particularly useful in the treatment of positive and negative symptomsof schizophrenia.

[0139] Evaluation of Catalepsy

[0140] By means of the test used for evaluating catalepsy in the rat,ST1699 affinity for the D₂ receptor subtype of the nigrostriataldopaminergic system was verified.

[0141] Table 4 gives the percentages of animals presenting catalepsy atthe various different times after administration of subacute doses ofthe study compound. TABLE 4 Time (minutes) of catalepsy evaluation afterAdministration mg/kg 30 min 60 min 90 min 120 min 180 min ST1699 0.6 3366  83 100 100 0.3  0  0  17  17  33 0.15  0  0  0  0  0 Haloperidol 0.2 0 70 100 100 100

[0142] The product ST1699 induced the occurrence of catalepsy as aresult of the highest dose among those used (0.6 mg/kg). The effectswere comparable to those induced by 0.2 mg/kg of haloperidol.

[0143] The occurrence of catalepsy only as a result of the highest dosemay indirectly verify the ability of the compound exemplified by ST1699to interact with the 5-HT_(2a) receptor. In fact, the antagonism to theabove-mentioned receptor modulates the dopaminergic activity of thenigrostriatal system, thus limiting the possibility of the occurrence ofcatalepsy.

[0144] Thus, on the strength of these results and its substantialreceptor affinity, the compound ST1508, alias ST1699, proves to be aclassic antipsychotic agent in which the dose necessary to obtain aneffective therapeutic response can be significantly reduced. Thanks tothis potential, the prolonged use of this product, in chronic diseasessuch as schizophrenia, would be associated with a better tolerability.

1. Formula (1) compounds

where: R=H, Cl, Br, F, I, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkyl,C₅-C₆ cycloalkyl; R₁=C₁-C₄ dialkylamine, where the alkyl groups can bethe same or different from one another, 4-alkyl-1-piperazinyl,4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl,4-alkyl-1-homopiperazinyl; R₂=H, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkyl, CHO, CH═NOH; R₃=H, CHO; and their pharmaceutically acceptablesalts.
 2. Compounds according to claim 1, wherein R₁ is4-alkyl-1-piperazinyl.
 3. Compounds according to claim 1, wherein R isH, Cl, Br, F, I.
 4. Compound according to claim 1, which is7-chloro-9-(4-methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepineand its pharmaceutically acceptable salts.
 5. Compound according toclaim 4, where the pharmaceutically acceptable salt is maleate. 6.Compounds according to claim 1, where R=H, F; R₂=H, CHO, CH₃; R₃=H;R₁=4-methyl-1-piperazinyl.
 7. Compounds according to claim 6, selectedfrom the group consisting of9-(4-methyl-1-piperazinyl)pyrrolo[2,1-b][1,3]benzothiazepine;7-fluoro-9-(4-methyl-1-piperazinyl)pyrrolo[2,1-b][1,3]benzothiazepine;1-methyl-9-(4-methylpiperazin-1-yl)pyrrolo[2,1-b][1,3]benzothiazepine.8. Compounds according to claims 1-7, for use as medicaments. 9.Pharmaceutical compositions containing a compound according to claims1-7 as an active ingredient in a mixture with at least onepharmaceutically acceptable vehicle and/or excipient.
 10. Use ofcompounds of claims 1-7 for the preparation of a medicament withantipsychotic activity.
 11. Use of compounds of claims 4 or 5 for thepreparation of a medicament with classic antipsychotic activity.
 12. Useof compounds of claims 6-7 for the preparation of a medicament with atypical antipsychotic activity.
 13. Use of compounds of claims 1-7 forthe preparation of a medicament useful for the treatment of conditionsof hyperactivation of dopaminergic neurotransmission.
 14. Use accordingto claim 13, in which the dopaminergic hyperactivity affects themesolimbic pathway
 15. Use of compounds of claims 1-7 for thepreparation of a medicament useful for the treatment of schizophrenia.16. Use of compounds of claims 1-7 for the preparation of a medicamentuseful for the treatment of the acute and chronic psychotic states. 17.Use of compounds of claims 6-7 for the preparation of a medicamentuseful for the treatment of disorders related to increased activity ofthe mesolimbic dopaminergic pathway and/or mesocortical dopaminergichypofunction.
 18. Use according to claim 17 for the preparation of amedicament useful for the treatment of schizophrenia in its positive andnegative symptoms.
 19. Use according to claim 17 for the preparation ofa medicament useful for the treatment of paranoid states,manic-depressive states, affective disorders, social withdrawal,personality regression, hallucinations or cognitive dysfunctions